title: Phase I trial of sorafenib in combination with ifosfamide in patients with advanced sarcoma: a Spanish group for research on sarcomas (GEIS) study.
abstract: BACKGROUND
  This phase I trial assessed safety, pharmacokinetics (PK), dose limiting toxicity (DLT), maximum tolerated dose and recommended dose (RD) of the combination of sorafenib plus ifosfamide in patients with advanced sarcoma.
  
  
  METHODS
  Twelve sarcoma patients (9 soft-tissue, 3 bone sarcoma) were treated with sorafenib plus ifosfamide (starting doses 200 mg bid and 6 g/m(2) respectively). A 3 + 3 dose escalation design with cohorts of 3-6 patients was used. A study to assess the in vitro efficacy of the combination was also conducted.
  
  
  RESULTS
  Three DLTs were observed: fatigue grade 4 with sorafenib 400 mg bid plus ifosfamide 6 g/m(2) and encephalopathy and emesis grade 3 with sorafenib 400 mg bid plus ifosfamide 7.5 g/m(2). Other toxicities included diarrhea, hand-foot syndrome, mucositis, neutropenia, skin rash and thrombocytopenia. There were no relevant effects on PK of sorafenib but an increase in ifosfamide active metabolite 4-hydroxy-ifosfamide was observed. Eight patients achieved stable disease lasting more than 12 weeks. An additive effect was observed in vitro.
  
  
  CONCLUSIONS
  RD was sorafenib 400 mg bid plus ifosfamide 6 g/m(2), allowing administration of active doses of both agents. Limited preliminary antitumor activity was also observed. A phase II study is currently ongoing.
authors.affiliation: Sarcoma Unit, The Royal Marsden Hospital, Fulham Road, SW3 6JJ, London, UK, juan.martin@rmh.nhs.uk.
authors.forename: J
authors.initials: J
authors.lastname: Martín-Liberal
authors.forename: A
authors.initials: A
authors.lastname: López-Pousa
authors.forename: J Martín
authors.initials: JM
authors.lastname: Broto
authors.forename: R
authors.initials: R
authors.lastname: Cubedo
authors.forename: O
authors.initials: O
authors.lastname: Gallego
authors.forename: E
authors.initials: E
authors.lastname: Brendel
authors.forename: O M
authors.initials: OM
authors.lastname: Tirado
authors.forename: X García
authors.initials: XG
authors.lastname: del Muro
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D012509:Sarcoma / Q000188:drug therapy* / Q000378:metabolism; D000077157:Sorafenib; D055815:Young Adult; D048490:raf Kinases / Q000037:antagonists & inhibitors
chemical_list: D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D000077157:Sorafenib; C039771:4-hydroxyifosfamide; D048490:raf Kinases; D007069:Ifosfamide